Mechanisms of Pathogenesis L4 Flashcards
what are the groups that pathogens are divided into
opportunistic pathogens
primary pathogens
what are opportunistic pathogens
Only cause serious disease when host defences are impaired
what are primary pathogens
Capable of causing disease in absence of immune defects
what do bacterial groups possess
virulence determinants which contribute to their ability to cause disease
if a pathogen has a single virulence is it pathogenic
Rarely is possession of a single virulence determinant sufficient to make a bacterium pathogenic
Virulence is Multifactorial relies on several things that the bacteria makes
what is the bacterial surface composition importance
mediates initial interactions with mammalian tissues and other surfaces
how the organism causes disease - bacterial virulence
what is the capsule
usually a polysaccharide layer, generally covers the whole bacterial surface
what is adhesion
fimbrae and pili are rod shape structures involved in sticking bacteria to surfaces
what are the envelope proteins for
some involved in adhesion, others involved in nutrient uptake, getting nutrient into the bacteria to grow
what contains lipopolysaccharide
only in gram negative bacteria
what is the function of lipopolysaccharide
Is important in immune invasion particularly complement invasion
Acts as a toxin, can induce damage
what happens between healthy to diseased
modulated by host immune responses
what happens when pathogen enters our tissues
immune system tries to remove
Bacteria can respond to get over the immune response
Dynamic equilibrium between the the bacteria and the immune system, depending which is ‘winning
what are the bacterial disease processes
- colonisation (adhesion, nutrient acquisition)
- tissue invasion
- avoidance of host defences
- tissue damage
- transmission
what is colonisation
First stage of disease process
Definition - Establishment of a stable population of bacteria in the host
where is bacteria available for colonisation
Source of bacteria is the environment, infected individuals or normal flora
what is the first interaction of bacteria in colonisation
Frequently on mucosal surface e.g respiratory tract (breathe organisms in), gastrointestinal tract (ingestion) or urogenital tract (sexual contact)
what is colonisation resistance caused by
Combination of host and bacterial factors which prevent colonisation by potential pathogens
examples of host factors that cause colonisation resistance
- low gastric pH
- bile
- proteases
- peristalsis
- salivary and mucous flow
- immunoglobulin A production
- macrophages
bacterial factors that cause colonisation resistance
Include competition by normal flora for space, nutrients and receptors and production by bacteria of fatty acids and bacteriocins
why are lactobacilli important in colonisation
Lactobacilli in breast milk colonise gut in new born babies and prevent infection by E.coli
In the vagina, Lactobacilli metabolise glycogen, resulting in a low pH, limits colonisation by potential pathogens
what can occur if interfere with colonisation resistance
disruption of normal bacterial flora may result in removal of competition and overgrowth of normal flora
in low amounts they are ok, but overgrowth can cause disease
can antibiotics help with interference with colonisation resistance
Treatment with antibiotics may lead to overgrowth of Clostridium difficile and Staphylococcus aureus in the gut and Candida albicans in the mouth
act as opportunistic pathogens
what could allow colonisation of organisms not usually found in a particular site
impairment of normal physiological functions
how may bacterial overgrowth in mouth occur
Dehydration may reduce salivary flow
what must bacteria be able to do in mucosal surfaces
mucosal sites are physiologically flushed e.g saliva in the mouth, peristalsis in the gut
bacteria must adhere to cell surfaces
Some bacteria adhere to other surfaces
what are the adherence stages
attachment
adhesion
Subsequent stages may result in aggregation to produce a biofilm - associated with biomaterials e.g catheters
what may happen to biofilms in adherence
Biofilms may disperse and seed new sites of infection
what happens in the attachment stage
non-specific physicochemical properties of the bacterium and the target surface - charge and hydrophobicity
Bacterial and mammalian cell surfaces usually both have a nett negative charge, only allows bacterium to approach cell surface within approx 10nm
what is the attachment phase like
reversible and mediated by weak ionic interaction such as hydrogen bonding and Van der Waal’s forces
what occurs in adhesion stage
involves specific interactions between bacterial surface components (adhesins) and mammalian cell surface receptors
Interaction allows bacterium to become intimately associated with cell surface - overcoming repulsive forces associated with charge effects
what is adhesion like
usually considered to be an irreversible process
what is the biofilm made up of
composed of bacteria and associated molecules form a matrix in which the bacteria are embedded
made up of bacterial cells and an extracellular matrix made of proteins, polysaccharide and DNA
what are bioflims
Once attached, some bacteria continue to grow in association with the surface to form a multi-layered biofilm
can biofilms be removed by antibiotics
antibiotics may not penetrate or work on all cells in the biofilm
how do biofilms cause infection throughout the body
Biofilms may also disperse – and cause infection at other body sites
how do phagocytic cells ingest bacteria in the biofilm
Phagocytic cells cannot easily ingest bacteria in a biofilm
what are conditioning films
biomaterials are implanted into tissue, they very quickly become coated with host proteins e.g fibrinogen, fibronectin
coating of host proteins is referred to as a conditioning film
what do the conditioning films do
bacteria can adhere to “bare” biomaterials in vitro, in tissues the conditioning film components probably act as the major receptors to which bacteria adhere
adhesin examples
Fimbriae - rod like protein adhesins e.g E. coli
Polysaccharide adhesins e.g oral streptococci
receptor examples
Blood group antigens
Extracellular matrix proteins (stick cells altogether) e.g fibronectin, collagen
what is essential for bacterial growth
iron
how much iron is available in our body for bacteria
Levels of free iron ion our tissues are very low (low as can be toxic to us)
not enough iron for need of bacteria
how do bacteria get enough iron for growth
bacteria express high affinity iron uptake systems
two main systems:
1. Siderophores
2. Direct binding of host iron transport proteins
what happens in the siderophore system
Bacteria sense not much iron available, switches on set of genes produce a siderophore, has a very high affinity of molecules with Fe3+ (ferric)
Siderophore interact with host tissue, has a higher affinity for the ferric than it does for the host tissue
Siderophore releases host tissue back into circulation, it uptakes the ferric
Goes to specific bacterial receptor on the surface, siderophore binds to receptor, is internalised into cell, iron is reduced to Fe2+
Fe2+ has lower affinity for siderophore, so is released and the bacteria can use it
Siderophore reused
what happens in the transferrin binding receptor mechanism
Bacterium makes a receptor on the surface that specifically recognises transferrin
Transferrin in circulation with the ferric attached binds to the bacterium receptor
Transferrin cant be taken into cell as too big, iron removed from surface and taken into cell and transferrin released
how is the Transferrin binding receptor mechanism limited
Only binds human transferrin – limits this organism
when are high affinity iron uptake systems in use
Only expressed under conditions of iron limitation e.g in mammalian tissues
what controls the expression of mechanisms for iron uptake
Expression controlled genetically by an iron dependent gene regulator called Fur
Fur = ferric uptake regulator
(controls amount of iron taken up as too much iron is also toxic for bacteria
what happens when there is a lot of iron in the body
Fur protein ferric uptake regulator binds to iron that available in cell forms a dimer – dimerisation
Binds to specific dna sequence
Bound to promoter blocks transcription of gene
what happens when there is not a lot of iron in body
deficient
no binding occurs
so gene can be transcribed to obtain iron from tissues
what is invasion
Some bacteria are able to penetrate into, through or between cells
why may invasion occur
may aid in survival and their spread to other body sites
where do bacteria invade
some bacteria can invade epithelial cells
others invade phagocytic cells
adhesion to specific receptors usually first stage in invasion
what are adhesins called
invasins
what do complements do
kills many Gram-negative bacteria
Complement and antibodies target bacteria for destruction, promoting phagocytosis and killing
what do cytokines do
allow cells to communicate with each other, can generate both antibody and phagocytic responses
how do gram negative bacteria avoid complement
cause sepsis are complement resistant
Resistance due to lipopolysaccharide (LPS) on the bacterial surface
Polysaccharide side chains of LPS sterically hinder access of activated complement components to the bacterial membrane
how can bacteria be complement resistant
Side chains prevent the membrane attack complex in the membrane
what happens if bacteria is not complement resistant
membrane attack complex
insert through bacterial membrane and forms a pore, internal contents of bacteria seep, loss of bacterial contents will kill the bacteria
can capsules aid avoidance of complements
prevent complement deposition or activation at an appropriate site e.g E.coli
Some bacteria also produce proteins which interfere with complement function - chemoattractant
protect against direct contact with complement
avoidance of antibodies using a bacterial capsule
prevent antibody binding or are weakly antigenic, so prevent efficient phagocytosis (so not recognised doesn’t initiate response to clear them)
Many different capsular types may be produced
avoidance of antibodies using antigenic variation
used by some bacteria to avoid binding of antibodies
Genetic mechanism allows it to change
New variant of protein is not recognised – avoid recognition
Why can be repeatedly infect
avoidance of antibodies using antigenic mimicry
Some bacterial capsules are identical to mammalian tissue molecules so are not recognised as foreign
Structure similar to structures in our tissues
Not to recognise self
If can coat in host tissue wont recognise
avoidance of antibodies using enzymatic digestion of antibodies
e.g Neisseria meningitidis produces an IgA protease
degrades IgA antibody on mucosal surfaces and prevents it from agglutinating bacteria
Produce enzymes – proteases that chop IgA, so antibody not functioning
prevents the agglutination of antibodies also
how do bacteria avoid phagocytes
Some bacteria produce toxins which kill phagocytes or inhibit their migration to sites of infection
Inherent physical properties of some bacterial capsules inhibit phagocytosis
how is the interaction of bacteria and phagocytes reduced further
hydrophilic capsule - phagocytic capsule like hydrophobic
affect of alpha toxins
High conc of alpha toxins kills
Low conc of alpha toxins inhibits their migration
how can some bacteria modify their response to cytokines
Some bacteria can modify normal cytokine responses and alter the immune response in favour of bacterial survival
Can interfere with direction immune response is directed – interfere with the cytokine response
how can tissue damage occur
- Direct effects of bacterial toxins
- Indirect effects of bacterial toxins
- Induction of autoimmune responses(own cells attack by own immune system) bacterium contains proteins and antigens, some are nearly identical to some in our body
what are the two types of bacterial toxins
exotoxins endotoxins (LPS)
what do exotoxins do
actions selective for specific biochemical targets
what do endotoxins do
activates many biochemical pathways - effects mediated by triggering of cytokine release from mammalian cells
what do cytokines do
released include TNF –α (stimulate further tissue damage)
High concentrations cause cell/tissue damage
what are exotoxins made by
gram +ve and -ve
what are endotoxins made by
gram -ve
what is an exotoxin
protein
what is an endotoxin
lipopolysaccharide
how are exotoxins released
secreted by living bacteria
how are endotoxins released
cell lysis
what happens to exotoxins and endotoxins when heated
exotoxins usually heat labile - proteins will denature
endotoxins usually heat stable
what toxoids (vaccines) are there for exotoxins and endotoxins
exotoxins - toxoids available
endotoxins - no toxoids
how lethal are exotoxins and endotoxins
exotoxins - potentially
endotoxins - lethal (higher conc)
how are bacterial exotoxins classified
molecular mode of action
what do type 1 exotoxins do
Bind to mammalian surface proteins and trigger transmembrane signals
what do type 2 exotoxins do
Pore or channel forming toxins
what do type 3 exotoxins do
Bind to surface receptors and translocate active component into the cell
where are exotoxins generally located
cytoplasm of bacterial cell
where are endotoxins generally located
outer membrane (surface layer of gram -ve bacteria)
what makes up lipopolysaccharide
lipid A
core oligosaccharide
o-polysaccharide
how is a pore formed in the membrane
Receptor on mammalian cell surface
Pore forming toxin bind
Aggregates to form multimer that forms a pore in the membrane
what is the lipid A function in LPS
anchors molecules into outer membrane – very hydrophobic
what is the o polysaccharide function
stop complement getting to bacterial membrane, also stimulate an immune response (can sometimes be protective)
what are some properties of LPS
- pyrogenic (gives you a fever)
- potentially lethal
- activates complement cascade (tissue damage)
- activates clotting cascade
- induces TNF - alpha production
- induces interelukin 1 production
what is transmission
Spread from host to host maintains bacterial pathogens in the population – otherwise they would die out if the infected host dies
what is horizontal transmission
via direct contact, air, food, water, insect vectors
why are spores able to survive in a lot of environments
survive in soil and water etc don’t dry out
what is vertical transmission
mother passing on infection to neonates in utero
